Age-related macular degeneration is the leading cause of incurable blindness in persons over 55 years of age. Approximately one in four persons age 65 or over have signs of age-related maculopathy, and about 7% of persons age 75 or over have advanced macular degeneration with vision loss. Unfortunately, treatment for macular degeneration is limited to laserphotocoagulation, which is effective only for a small subset of those suffering the disease.
Macular degeneration is a degeneration of the macular region of the retina. The macular region of the retina is located in the center of the retina and includes the fovea, where the cone photoreceptor cells reach their greatest density. The macular region of the retina provides the greatest degree of visual acuity in the retina, and degeneration of the macula causes the loss of acute vision.
The exact causes of macular degeneration are not known, however, contributing factors have been identified. The collective result of the contributing factors is a disturbance between the photoreceptor cells and the tissues under the retina which nourish the photoreceptor cells, including the retinal pigment epithelium, which directly underlies and supports the photoreceptor cells, and the choroid, which underlies and nourishes the retinal pigment epithelium.
One factor which has been identified as contributing to macular degeneration is reactive oxidants, such as free radicals and singlet oxygen (.sup.1 O.sub.2), which cause oxidative damage to the cells of the retina and the macula. The retina may be prone to oxidative damage as a result of the large degree of oxidation-susceptible polyunsaturated fatty acids present in the retina.
The macula may be particularly prone to oxidative damage since the macula is especially rich in polyunsaturated fatty acids and is exposed to a relatively high degree of high-energy blue light. Triplet oxygen, or ground state oxygen, absorbs high-energy blue light to convert to singlet oxygen, an oxidizing agent capable of damaging the polyunsaturated fatty acids, DNA, proteins, lipids, and carbohydrates in the macula. Blue light may also generate free-radical oxidizing agents by photochemical reactions with other compounds in the eye. The oxidized by-products from interactions between the retina and oxidative agents may accumulate in the retinal pigment epithelium, contributing to macular degeneration.
Another factor which may be involved in the pathology of macular degeneration is a high serum low density cholesterol lipoprotein (LDL) concentration. Low density lipoprotein cholesterol can be oxidized by an oxidizing agent to form oxidized LDL, a compound found in atherosclerotic plaques. As noted above, oxidizing agents can be generated in the macula by high energy light, and these oxidizing agents can interact with LDL to form oxidized lipid products. These products may accumulate as deposits in healthy retinal pigment epithelium and cause necrosis or death of functioning tissue. LDL cholesterol may also form atherosclerotic plaques in the blood vessels of the retinal and subretinal tissue, inducing hypoxia in the tissue, resulting in neovascularization.
Another factor which has been identified as contributing to macular degeneration, and which is an indication of advanced macular degeneration, is neovascularization of the choroid tissue underlying the photoreceptor cells in the macula. Healthy mature ocular vasculature is normally quiescent and exists in a state of homeostasis in which a balance is maintained between positive and negative mediators of angiogenisis (development of new vasculature). Macular degeneration, particularly in its advanced stages, is characterized by the pathological growth of new blood vessels in the choroid underlying the macula. Angiogenic blood vessels in the subretinal choroid often leak vision obscuring fluids, leading to blindness.
Angiogenisis in the choroid is induced by the presence of cytokine growth factors such as basic fibroblast growth factor (bFGF). Hypoxia of retinal cells is one factor which may induce the expression of such growth factors, where the hypoxia may be induced by cellular debris (drusen) accumulated in the retinal pigment epithelium, oxidative damage of retinal and subretinal tissue, or deposits of oxidized LDL cholesterol.
Existing retinal and subretinal vascular endothelial cells are activated by interaction of the cytokine growth factors, particularly bFGF, with tyrosine kinase mediated receptors of the endothelial cells. The activated endothelial cells increase in cellular proliferation and express several molecular agents, including the integrin .alpha..sub.v .beta..sub.3, adhesion molecules, and proteolytic enzymes, which enable newly developed endothelial cells to extend through the surrounding tissue. The newly extended endothelial cells form into vascular cords and eventually differentiate into mature blood vessels.
Several factors have been identified as protective factors against macular degeneration which substantially reduce the risk of developing the disease by interfering with the action of the contributing factors described above. Estrogen has been identified as a protective factor, and postmenopausal women given unopposed estrogen replacement therapy have a reduced risk of neovascular age-related macular degeneration. Evidence for Protection Against Age-Related Macular Degeneration by Carotenoids and Antioxidant Vitamins, Snodderly, Am J Clin Nutr 1995;62 (suppl): 1448S-61 S, 1454S. Estrogen is known to increase high density lipoprotein cholesterol (HDL) in the blood, which may produce changes in the transport and metabolism of lipid-soluble antioxidants, thus limiting the accumulation of oxidized LDL cholesterol in the retinal and subretinal tissues and blood vessels.
Certain antioxidant nutrients are also associated with a substantially reduced risk of developing macular degeneration. Protective antioxidants reduce the formation of radicals and reactive oxygen by decomposition of hydrogen peroxide without generating radicals, by quenching active singlet oxygen, and by trapping and quenching radicals before they reach a cellular target. An increased intake of the dietary antioxidants lutein and zeaxanthin, which are caroteinoids found in spinach, has been found to be protective against macular degeneration. Dietary Caroteinoids, Vitamins A, C, and E, and Advanced Age-Related Macular Degeneration, Seddon et al., JAMA, 272(18): 1413-20 (Nov. 9, 1994). High blood levels of antioxidant vitamins C and E have also been shown to be protective against macular degeneration. Evidence for Protection Against Age-Related Macular Degeneration by Carotenoids and Antioxidant Vitamins, Snodderly, Am J Clin Nutr 1995;62 (suppl): 1448S-61S, 1453S.
Treatment of advanced macular degeneration with integrin antagonists to inhibit angiogenisis in the subretinal tissues has also been proposed. Involvement of Integrins .alpha..sub.v .beta..sub.3 and .alpha..sub.v .beta..sub.5 in Ocular Neovascular Diseases, Friedlander et al., Proc. Natl Acad. Sci. USA 93:9764-69 (Sept. 1996). Integrin .alpha..sub.v .beta..sub.3 is necessary for angiogenisis in retinal tissue, and is only found in actively proliferating vascular endothelial cells. Peptide antagonists of .alpha..sub.v .crclbar..sub.3 have been shown to substantially inhibit development of new retinal vasculature in mice.